Free Radicals

Ubiquinol as an antioxidant

The role of ubiquinol as an antioxidant is much more controversial than its role in ATP synthesis (Beyer, 1992). In liposomes, ubiquinol has antioxidant ability similar to that of alpha-tocopherol but, unlike alpha-tocopherol, is not recycled by vitamin C (ascorbate) (Frei et al., 199O Shi et al., 1999). There is, however, evidence suggesting that the semiquinone form of CoQ1O may be a pro-oxidant and generate superoxide radicals (Beyer, 1992). In vitro data suggest, however, that CoQ1O can conserve vitamin E in rat liver microsomes and mitochondrial membranes and thereby increase the resistance of these membranes to oxidative damage (Hiramatsu et al., 1991). Dietary supplementation with CoQ1O is known to increase the level of ubiquinol in LDL and to increase the resistance of LDL to the initiation of lipid peroxidation (Mohr et al., 1992). As detailed above, the ability of dietary antioxidants to prevent the formation of oxLDL may be an important factor in preventing the very early...

Depletion of Endogenous Antioxidants and Altered Activity of Antioxidant Enzymes

Depletion of endogenous antioxidants and free radical scavengers may occur in diabetes (28,96-101). In plasma or serum, lower levels of vitamins C, E, and A, lycopene, and lipoic acid have been reported in human diabetics compared with non-diabetic controls (28,96-99,102-104). Similarly, impaired total serum antioxidant capacity and reduced antioxidant properties of serum albumin and high-density lipoprotein have been described in human diabetics (102,105-109). In experimental diabetes, depletion of reduced glutathione occurs in kidney and other tissues (36,49,70). Depletion of endogenous antioxidants and radical scavengers in diabetes may be a consequence rather than a cause of oxidative stress. Depending on the tissue examined and the duration and severity of diabetes, activities of some antioxidant enzymes are reduced, whereas those of others are increased or unchanged (14,38,110-117). Thus, activities of both cytosolic Cu2+ Zn2+ SOD (SOD1) and mitochondrial Mn2+ SOD (SOD2) of...

Dietary prevention of sudden cardiac death SCD the role of dietary fatty acids alcohol and antioxidants

We now examine whether diet (and more precisely, certain dietary factors) may prevent (or help prevent) SCD in patients with established CHD. We focus our analyses on the effects of the different families of fatty acids, antioxidants and alcohol.2 Support for the hypothesis of a clinically significant antiarrhythmic effect of n-3 PUFA in the secondary prevention of CHD, as put forward in DART,3 came from two randomised trials testing the effect of ethnic dietary patterns (instead of that of a single food or nutrient), i.e. a Mediterranean type of diet and an Asian vegetarian diet, in the secondary prevention of CHD.18'19 The two experimental diets included a high intake of essential alpha-linolenic acid, the main vegetable n-3 PUFA. Whereas the incidence of SCD was markedly reduced in both trials, the number of cases was very small and the antiarrhythmic effect cannot be entirely attributed to alpha-linolenic acid as these experimental diets were also high in other nutrients with...

Optimizing the Antioxidant Network

You may obtain greater benefits by taking multiple antioxidants in addition to vitamin E. According to Lester Packer, Ph.D., of the University of California, Berkeley, antioxidants work best as a team. Antioxidants get used up rapidly fighting free radicals, but a diversity of antioxidants helps them regenerate to full strength. Many different antioxidants also help neutralize many different types of free radicals, with the result often being a faster recovery time. For example, physicians at Loyola University Medical Center, Chicago, found that a combination of vitamins E and C reduced radiation proctitis a type of rectal inflammation caused by radiation treatment. As another example, Italian researchers reported that hereditary pancreatitis, a painful recurring inflammation of the pancreas, could be reduced by a combination of vitamins E and C, selenium, and other antioxidants.

Vitamin E and other antioxidants in the prevention of cardiovascular disease

Although enzymatic and nonenzymatic oxidation of LDL seems to be involved, its relevance in the evolution of human atherosclerosis is still unclear. An important matter of discussion is the evident discrepancy between experimental and clinical trials with antioxidants, that, in fact, provided divergent results. Most trials with antioxidants in experimental models of atherosclerosis demonstrated that this treatment is able to retard the progression of atherosclerosis while the results of clinical trials are conflicting,5 in that positive as well as negative effects has been reported. The investigation of antioxidants for prevention of atherosclerosis stems from observational trials that demonstrated the existence of an inverse relationship between the consumption of antioxidant vitamins and the risk of cardiovascular events. However, meta-analysis of the observational studies indicated that among antioxidant vitamins, vitamin E was the only one that exerted a beneficial effect against...

Antioxidants cardiovascular disease and oxidative modifications of lowdensity lipoprotein

Both lipid-soluble and water-soluble antioxidants present in blood may be important in preventing cardiovascular disease owing to their ability to prevent the oxidation of lipid-protein complexes called lipoproteins. Lipoproteins are extremely important in cardiovascular disease since we know with certainty that high levels of LDL-C cause atherosclerosis, which is the underlying cause of most cardiovascular disease. In contrast, high levels of HDL-C are a negative risk factor for CVD. Atherosclerosis is the gradual build-up of 'plaque' in the arterial wall. LDL-C is the major source of the lipids occurring in these plaques. LDL is the primary plasma carrier for both vitamin E and CoQIO, both of which act as antioxidants in LDL by inhibiting lipid peroxidation of lipids containing polyunsaturated fatty acid moieties. Work by Jessup et al. (199O) indicates that most of the endogenous vitamin E in LDL must be oxidized before it is converted into a 'high uptake' form of oxLDL capable of...

Dr Kunin and Susan Antioxidants for Health

Kunin then developed an antioxidant and anticoagulant regimen for Susan to follow, based in part on the fact that vitamin antioxidants also have blood-thinning properties. Use of bromelain supplements served as a natural way to reduce blood viscosity (caused by excessive fibrin), as did use of small oral amounts of heparin, an anticoagulant drug. Heparin, Kunin explained, has anticoagulant effects when taken orally (not just by injection) but does not interfere with vitamin K metabolism the way Coumadin does.

Vitamin D as an antioxidant

Work by Wiseman (1993) has shown that vitamin D3 (cholecalciferol), its active metabolite 1,25-dihydroxycholecalciferol, Vitamin D2 (ergocalciferol), and 7-dehydrocholesterol (pro-Vitamin D3) are all membrane antioxidants by virtue of their abilities to inhibit iron-dependent liposomal lipid peroxidation. There are very few studies focusing on the potential role of vitamin D as an antioxidant in biological systems. One such study by Sardar et al. (1996) found that vitamin D3 may function as an in vivo antioxidant in the rat liver with an effectiveness higher than that observed with vitamin E supplementation. It is unlikely that vitamin D in plasma could be an effective antioxidant since its levels are very low, i.e. the levels of 25 (OH)D3 and other vitamin D metabolites in healthy persons are between 6O and 1OOnM. In contrast, plasma vitamin E levels are between 15 3O y M, which is at least 25O times higher than the typical plasma levels of vitamin D. At present, there are no data...

Dietary antioxidants and the prevention of CHD epidemiological evidence

A large number of epidemiological studies have evaluated potential relationships between dietary intake of antioxidants and coronary heart disease (CHD). These are summarised in Table 5.1. Among these, the Nurses' Health study,36 included over 87 000 female nurses 34 to 59 years of age, who completed dietary questionnaires that assessed their consumption of a wide range of nutrients, including vitamin E. During follow-up of up to 8 years 552 cases of major coronary disease were documented. As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, including other antioxidants, had little effect on the results. Similarly, the Health Professionals' Follow-up study, among almost 40 000 males of 40-75 years, followed up for four years, showed a lower risk of coronary...

Dietary antioxidants and the prevention of CHD evidence from clinical trials

While most epidemiological studies have demonstrated that dietary intake of vitamin E is inversely related to coronary heart complications, supplementation studies gave conflicting results. Clinical trials with antioxidants have been done in patients with or without previous history of cardiovascular disease (Table 5.2). Surrogate endpoints, such as analysis of atherosclerosis progression, or 'hard' endpoints, such as vascular death and MI, have been used to evaluate the clinical benefits of antioxidant vitamins. The Alpha-Tocopherol-Beta-Carotene-Cancer (ATBC)52 prevention study was a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta-carotene or both reduced the incidence of lung cancer and other cancers. A total of 29 133 male smokers, 50-69 years of age, were randomly assigned to one of four regimens alpha-tocopherol (50 mg per day) alone, beta-carotene (20 mg per day) alone, both...

Cynthia Antioxidants to Treat Hepatitis

Berkson started Cynthia on his triple antioxidant approach, which included 600 mg of alpha-lipoic acid, 400 mcg of selenium, and 900 mg of silymarin daily. He also asked her to follow a diet similar to the AntiInflammation Syndrome Diet Plan, rich in protein and vegetables and low in refined carbohydrates. After two weeks she had an increase in energy and was able to resume many normal activities. By the sixth week of supplementation Cynthia's liver enzymes had fallen to near-normal levels and her fasting glucose was 112 mg dl. She has been following the diet and supplement regimen for more than five years and reports that she still feels great.

Antioxidant Therapy

The effects of dietary supplementation with exogenous antioxidants on renal injury in experimental diabetes have been extensively examined (36,162-165). Agents studied include vitamins E and C, lipoic acid, and taurine (36,162-165). Most studies have found renoprotective effects associated with evidence of reduced oxidative stress, including reduction in indices of renal lipid peroxidation and restoration of renal cortical levels of reduced glutathione (36,162-165). Lipoic acid, in particular, has been shown not only to suppress albumin excretion, glomerular volume, and glomerular content of TGF-P and collagen (a1) IV, but also to attenuate subsequent increases in mesangial matrix volume and glomerulosclerosis (36,165). However, not all studies have found that conventional antioxidants ameliorate DN in experimental models (163). The dose of antioxidants employed may be critical, perhaps because agents such as vitamin E may have either pro- or antioxidant effects in vivo (164). Thus,...


Several studies have proposed various antioxidants as anti-AGE agents, including vitamin E (167), -acetylcysteine (168), taurine (169), a-lipoic acid (170), penicillamine (171), and nicarnitine (172). Also, pyruvate is a potent scavenger of ROS such as H2O2 and O2- that also minimizes the production of OH by the Haber-Weiss reaction. Additionally, it inhibits the initial reaction of glucose with free amino groups that results in Schiff base formation, as documented by in vitro data (173,174). Despite the existing data, however, further studies are needed to establish the effectiveness of treatment with antioxidants as a strategy in reducing AGE levels.

Oxygen Free Radicals

Oxygen free radicals, formed as a by-product of many chemical reactions in the body, wreak havoc wherever they go. Normally, the body has ways of quenching free radicals. But smoke, air pollution, diet, and even genetics can contribute to the formation of excessive amounts of free radicals, which the body cannot always handle. Uncontrolled, the reactive molecules can destroy the body's own cells as well as bacteria. Oxygen free radicals contribute significantly to the aging process and to the development of several other diseases. Researchers have implicated free radicals in the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, a degenerative neuromuscular disease. Some researchers believe that oxygen free radicals may also contribute to type 1 diabetes. Islet cells have very low levels of the enzymes that break down free radicals. Thus, agents that increase free radical production could result in destruction of pancreatic cells. If this is true, then...

Vitamins and minerals

A well-balanced diet does not need supplementation of vitamins and minerals. Only in certain cases such as illness, stress or pregnancy is a higher intake required. High doses of dietary antioxidants such as vitamins C and E, selenium, beta-carotene and other carotenoids have been prescribed to people with diabetes.29 Antioxidants are substances that neutralize the action of free radicals, which are molecules that damage cells, and increase the risk of cancer and heart diseases. In this case they are thought to protect LDL particles from oxidation. However, according to the ADA dietary guidelines, 'routine supplementation of the diet with antioxidants is not advised because of uncertainties related to long-term efficacy and safety'.

Understanding oxidative stress

In recent years, the research disciplines interested in oxidative stress have grown and enormously increased our knowledge of the importance of the cell redox status and the recognition of oxidative stress as a process with implications for many pathophysiological states. From this multi- and inter-disciplinary interest in oxidative stress emerges a concept that attests to the vast consequences of the complex and dynamic interplay of oxidants and antioxidants in cellular and tissue settings. Consequently, our view of oxidative stress is growing in scope and new future directions. Likewise, the term reactive oxygen species adopted at some stage in order to highlight non-radical oxidants such as H2O2 and 1O2 now fails to reflect the rich variety of other reactive species in free radical biology and medicine encompassing nitrogen- , sulfur- , oxygen- , and carbon-centered radicals. With the discovery of nitric oxide, nitrogen-centered radicals Virtually all diseases thus far examined...

Woo Je Lee KiUp Lee and Joong Yeol Park contents

Recent evidence suggests that oxidative stress plays a causative role in many chronic diseases such as diabetes and cardiovascular disease. Many efforts have been made to prevent the development and progression of diabetes and cardiovascular disease by using materials with antioxidative properties. Among a variety of antioxidants, a-lipoic acid (a-LA) has recently received much research attention. This chapter will focus on the roles and mechanisms of a-LA in the prevention of diabetes mellitus and endothelial dysfunction in obese animals.

Vitamin E and measures of cardiovascular function

Despite the mixed results when the outcome measures are myocardial infarction or stroke, there is considerable evidence that vitamin E has a positive effect on other measures of cardiovascular function. For example, a study by Skyrme-Jones et al. (2000) found that 1000 IU of vitamin E (all-racemic alpha-tocopherol) for 3 months improved endothelial function and blood flow in patients with type I diabetes and reduced the oxidative susceptibility of LDL. This study had an excellent study design, i.e. double-blind, placebo-controlled, and randomized. The relationship of oxidative stress to diabetes and the potential use of antioxidants is an area of intensive research (Laight et al., 2000). Owing to an epidemic of childhood obesity, the incidence of type II diabetes is expected to dramatically increase in the near future.

Sources of further information and advice

Antioxidants, statins, and atherosclerosis. J Am Coll Cardiol 2003 41(7) 1205-10. 3. steinberg d, witztum jl. Is the oxidative modification hypothesis relevant to human atherosclerosis Do the antioxidant trials conducted to date refute the hypothesis Circulation 2002 105(17) 2107-11. 7. carroll mf, schade ds. Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation. 2003 108(1) 24-31.

General Dietetic Advice For Pregnancy

Once pregnancy has been confirmed the diet should be reviewed to ensure the recommended vitamin and mineral intakes, including folate and iron, for pregnancy are met. Ensuring adequate amounts of antioxidants in the diet may help to lessen the risk of pre-eclampsia and congenital malformation. Recently dietary supplementation with the antioxidant vitamins C and E have been shown to reduce the incidence of pre-eclampsia in high-risk women (15). Animal, but so far not human, studies have shown that these vitamins also protect embryos from the teratogenic effects of hyperglycaemia (16).

Vitamin C and Inflammatory Disorders

In particular, vitamin C (like many other antioxidants) appears to dampen inflammation by quenching free radicals and reducing the activity of pro-inflammatory adhesion molecules. Conversely, inadequate intake of vitamin E is associated with inflammatory disorders. For example, a re

Oxidative Stress and Inflammation

Oxidative stress of the placenta, due to hypoxia, may lead to endothelial dysfunction (80, 81). F2-isoprostanes are considered to be the best in vivo marker of lipid peroxidation, and they are products of free radical attacks on arachidonic acid (82, 83). In a study measuring F2-isoprostanes, they were found to be elevated in women with preeclampsia and remained elevated up to 6 weeks postpartum (84). In preeclampsia, plasma levels of free-8 isoprostanes are elevated compared with those with a normal pregnancy (85, 86). Breath methylated alkanes are measures of oxidative stress and have also been found to be elevated in women with preeclampsia (87). Given the suggestion that oxidative stress may be an underlying etiology of preeclampsia, studies using antioxidants to prevent preec-lampsia were performed however, these found that vitamin C and vitamin E did not reduce the risk of preeclampsia in high- and low-risk women (88, 89).

Dietary prevention of chronic heart failure CHF the role of micronutrients dietary fatty acids and reduced sodium intake

The incidence of chronic heart failure (CHF), the common end-result of most cardiac diseases, is increasing steadily in many countries despite (and probably because of) considerable improvements in the acute and chronic treatment of CHD, which is nowadays the main cause of CHF in most countries.52 In recent years, most research effort about CHF has focused on drug treatment, and little attention has been paid to nonpharmacological management. Some unidentified factors may indeed contribute to the rise in the prevalence of CHF and should be recognised and corrected if possible. For instance, CHF is now seen also as a metabolic problem, with endocrine and immunological disturbances potentially contributing to the progression of the disease.53'54 In particular, the role of the tumour necrosis factor (TNF) is discussed below. Recently it has also been recognised that increased oxidative stress may contribute to the pathogenesis of CHF.55 The intimate link between diet and oxidative stress...

Pathogenic mechanisms of ironinduced atherosclerosis

As a redox active metal, iron is capable of catalysing the formation of hydroxyl radicals in the Fenton reaction (Marx & van Asbeck 1996). Several antioxidants have been shown to protect against the endothelial dysfunction associated with atherosclerosis (Diaz et al. 1997). The oxygen radicals may involve in the regulation of nuclear factor KB (NF-k ) DNA binding (Baldwin 2001), important for the transcription of a large number of genes, including the endothelial adhesion molecules (Collins et al. 1995 Neish et al. 1992).

Other Growth Factors and Regulation of mRNA Translation Vascular Endothelial Growth Factor VEGF

The rapidity of angiotensin II regulation of VEGF synthesis suggested involvement of a mediator that is recruited almost immediately on exposure to angiotensin II. In this context, the role of reactive oxygen species (ROS) was examined. Angiotensin II has been shown to stimulate Akt by activation of ROS in mesangial cells (111,112). Angiotensin II-induced VEGF synthesis was completely inhibited by antioxidants -acetyl cysteine and diphenyleneiodonium. Further investigation showed that ROS were upstream of PI 3 kinase-Akt-4E BP1 pathway in angiotensin II-treated cells (112a). The source of ROS that results in injury to target tissues in diabetes has attracted attention. A unifying scheme in which ROS originate in the mitochondria has been proposed as the underlying mechanism of target cell injury in diabetes (113). However, amelioration of angiotensin II effect on VEGF synthesis by diphenyleneiodonium suggested involvement of flavin-containing NAD(P)H oxidase as a possible source of...

Interactions Between ROS and NO

NO also modulates the proliferation of MC and production of ECM in response to HG, Ang II, and other stimuli (146-149). Thus, altered NO signaling may also participate in the expansion of glomerular mesangium characteristic of DN. In general, evidence in cultured MC and VSMC supports antiproliferative actions of NO and NO suppression of ECM protein production by MC (146-152). Studies in cultured MC have shown that increases in endogenous NO production or NO donors can suppress several steps in the signaling cascade by which HG, Ang II, and TXA2 increase ECM production, including activation of PKC and increases in TGF-P (146,148,149). As noted above, some of these same agonists increase ROS generation in MC (81,131,135). Thus, expression of the action of HG and Ang II to increase MC matrix protein may be owing, in part, to quenching of NO by ROS. This conclusion is supported by the action of antioxidants to potentiate NO suppression of MC synthesis of ECM in response to HG (148)....

HMG CoA Reductase Inhibitors

The normal endothelium plays an important role in the prevention of atherosclerosis and microvascular disease. DM is an important cause of both macro- and microvascular disease. Animal and clinical studies have demonstrated a decrease in endothelium-de-pendent vasodilation in both type 1 and type 2 DM. Possible mechanisms include abnormalities in signal transduction, reduced synthesis of NO, accelerated inactivation of NO, or production of vasoconstrictor prostanoids, probably through the relative increase of oxygen-derived free radicals (Table 1). The mediators of this abnormality include hyperinsulinemia, insulin resistance, or hyperglycemia. Improved glucose control, supplementation with either tetrahydrobiopterin, L-arginine, or vitamin C, or the addition of ACE inhibitors have been shown to improve endothelial function. Further research is required to determine whether restoring endothelial function in patients with either type 1 or type 2 diabetes will translate into an overall...

Inhibitors of AGE Formation and RAGE Blockade

In STZ diabetic rats, two structurally different inhibitors of AGE formation have been reported to ameliorate renal injury (124,156-158). Aminoguanidine, the most extensively studied inhibitor of AGE formation, has been reported to prevent the development of albuminuria and mesangial matrix expansion, as well as renal accumulation of AGE (124). Similarly, this agent has been reported to prevent retinal and neural injury in experimental diabetes (34,159). In addition to its antioxidant properties, aminoguanidine also inhibits the activity of inducible NOS (124,150, 157). However, a recent study suggests that its renoprotective actions in diabetes are owing largely to its antioxidant properties (124). Clinical trials with aminoguanidine in human diabetics with nephropathy have found a reduction in proteinuria and retardation of loss of renal function (34), but drug toxicity has complicated interpretation of these benefits (6). Consistent with the possibility that extracellular AGE...

Apart from the potency what other characteristics of insulin secretion differentiate the second generation

Been incriminated for the appearance of events that can be related with insulin resistance (myocardial infarctions and strokes). The UKPDS study did not confirm the researchers' concern on this point and it is likely that hyperinsulinaemia constitutes only an indicator for the macrovascular complications and not the direct reason. The newer sulfonylureas glipizide, gliclazide and glimepiride bring about a smaller secretion of insulin than glibenclamide. The insulin secretion after ingestion of gliclazide and glimepiride varies during the day, following the postprandial insulin requirements. Glibenclamide causes a slow, steadily increasing secretion of insulin from the isolated pancreas, and gliclazide causes a two-phase secretion of insulin and a more rapid return to baseline. In other studies, gliclazide inhibited the oxidation of LDL particles and caused an increase of the antioxidant properties of the plasma both in-vitro and in-vivo, in contrast to many other sulfonylureas.

Nutritional risk factors in the onset and prevention of type diabetes

Obesity and sedentary lifestyle are well-established risk determinants of type 2 diabetes (Costacou & Mayer-Davis 2003). Recently two randomised trials provided evidence that type 2 diabetes can be prevented by changes in diet and in exercise pattern in men and women at high risk of the disease (Tuomilehto et al. 2001 Diabetes Prevention Program Research Group 2002). The beneficial role of dietary fibre and a harmful one of saturated fatty acids seem to be rather well shown, whereas evidence is contradictory as to whether dietary or supplementary antioxidant vitamins or minerals prevent the disease. Discussion on optimal proportions of fat and carbohydrate in the diet for the prevention of type 2 diabetes continues. Attention is increasingly paid to different types of fat and carbohydrate. Also, attempts to individualise the advice according to metabolic status have decreased the discrepancies in views (Grundy et al. 2002).

Oxidative stress at childbirth

Neonatal plasma has relatively poor antioxidative defenses.62 At birth, neonatal plasma concentrations of vitamins A, E and p-carotene were significantly lower than maternal plasma levels, while neonatal levels of vitamin C were significantly higher.63 Uric acid and vitamin C constitute most of the extracellular antioxidant capacity, totaling 75 . At 2 weeks of age, these two components represent only 35 of the extracellular capacity. This change is caused by the rapid decline of vitamin C levels during the first few days of life and the increasing concentration of bilirubin which acts as an antioxidant in the first 1 to 2 weeks post-partum.64

Oxidative and Nitrosative Stress in Diabetic Cardiomyopathy

There is circumstantial clinical and experimental evidence suggesting that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia functional hypoxia, and elevated circulating levels of glucose result in oxidative and nitrosative stress in cardiovascular system of diabetic animals and humans. Oxidative stress associated with an impaired antioxidant defense status may play a critical role in subcellular remodeling, calcium-handling abnormalities, and subsequent diabetic cardiomyopathy (75,89). Oxidative and nitrosative damage may be critical in the early onset of diabetic cardiomyopathy (74,75). Consistent with this idea, significant nitrotyrosine formation was reported in cardiac myocytes from myocardial biopsy samples obtained from diabetic and diabetic-hypertensive patients (74) and in a mouse model of streptozotocin (STZ)-induced diabetes (75). Perfusion of isolated hearts with high glucose caused a significant upregulation of iNOS, increased...

The Complexity of Sex Steroid Actions

The mechanism of action of both estrogens and progestogens on the vascular system is diverse and complex. Some of the estrogen actions, including those on the atherogenic lipoproteins, antioxidant activity and enhancement of endothelial function are unequivocally antiatherogenic. Some of these effects, however, may be partly negated by certain synthetic progestogens used in conventional HRT. On the other hand, the net clinical effect of the prothrombotic vs fibrinolytic actions of estrogens may vary depending on dose, route of administration, the state of the vascular wall and genetic factors, so that in certain circumstances the prothrombotic effects may predominate resulting to thrombosis.

Lipoprotein Glycation Oxidation and Glyco Oxidation

It has been postulated that enhanced glycation, oxidation, and glyco-oxidation of lipoproteins may underlie the development of macrovascular disease in diabetes. This is quite an attractive hypothesis because it would explain the individual variation in the development of complications in diabetes. Regardless of the similarity in glycemic control and cardiovascular risk factors, the development of complications would also depend on differences in oxidative stress and variations in the antioxidant defenses and in differences in the immune response to the modified lipoproteins. A short summary of the large body of evidence showing that modified lipoproteins may be relevant to the accelerated development of atherosclerosis in diabetes is presented next.

Treatment targeting TGFP

The antioxidant a-tocopherol blocks the high-glucose-induced increase in PKC, TGF-p and matrix accumulation in vitro in mesangial cells.178 In addition, a-tocopherol administered to STZ-diabetic rats prevents the increase in glomerular TGF-p immunoreactivity and reduces glomerular size, but it has no effect on albumin clearance.107 LY333531, a specific PKCp isoform inhibitor, abolishes the diabetes-associated increase in glomerular TGF-p mRNA, matrix accumulation and renal vascular dysfunctions89 when given to STZ-diabetic rats for 3 months.89,95 In a long-term study in diabetic db db mice, PKCp inhibition results in the reduction of long-term renal changes, including the increase in glomerular TGF-p1

Apoptosis as a Mechanism of pCell Death

Apoptosis or programmed cell death is an integral part of tissue homeostasis and apoptotic cells are rapidly cleared from tissues by scavenger macrophages or by immature dendritic cells to prevent inappropriate inflammatory responses. Apoptosis refers to the morphological features of programmed cell death, which is a normal process contributing to tissue turnover during development and in the adult. Traditionally, apoptosis is not expected to be associated with a subsequent immune response. Cells that undergo apoptosis are characterized by shrinkage, nuclear condensation, membrane blebbing, and membrane changes that eventually lead to phagocytosis of the affected cell. The possible role of apoptosis in type 1 diabetes pathogenesis has recently been reviewed (122,123). The following signaling pathways have been implied in apoptosis the Fas system, stress-activated protein kinases, serine threonine kinases, the Ras signaling pathway, protein kinase C, calcium signaling pathways,...

Free Fatty Acids and Nitric Oxide

The free FAs act to decrease endothelial function probably by several pathways including increased production of oxygen-derived free radicals, activation of PKC, and decrease insulin receptor substrate-1-associated phophatidylinositorl-3 kinase activity (131-133). This action may decrease NOSynthase activity via its effect on signal transduction.

What Is Dental Inflammation

There is a good chance that you have gingivitis. Periodontitis describes inflammation that is much deeper and involves the supporting bone of the teeth, and it is often missed in casual examinations. Periodontitis erodes the bone forming teeth. TMJ syndrome is generally recognized as a misalignment of the temporomandibular joint, located near the ears, which hinges the jawbone to the skull. This misalignment generates free radicals, which can fuel inflammation.

Oxidative and Nitrosative Stress in Diabetes Induced Vascular Dysfunction

Various neurohumoral mediators and mechanical forces acting on the innermost layer of blood vessels, the endothelium, are involved in the regulation of the vascular tone. The main pathway of vasoregulation involves the activation of the constitutive, endothelial isoform of NO synthase (eNOS) resulting in NO production (53). Endothelium-depen-dent vasodilatation is frequently used as a reproducible and accessible parameter to probe endothelial function in various pathophysiological conditions. It is well established that endothelial dysfunction, in many diseases, precedes, predicts, and predisposes for the subsequent, more severe vascular alterations. Endothelial dysfunction has been documented in various forms of diabetes, and even in prediabetic individuals (52,54-58). The pathogenesis of this endothelial dysfunction involves many components including increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol, and the subsequent activation of...

AGEs And Oxidative Stress

Elevated oxidative stress seen in diabetes is viewed to be the result of both an increase in ROS generation and a decrease in endogenous anti-oxidant activity including free radical scavengers and enzyme systems 54 . AGEs lead to enhanced formation of free radicals both directly through catalytic sites in their molecular structure 58 and via stimulation of membrane-bound NAD(P)H oxidase through the RAGE receptor 59 . In addition, AGE-dependent depletion of cellular anti-oxidant systems such as glutathione peroxidase are also inhibited by antibodies to AGER1, AGE-R2 as well as RAGE 57 . Mitochondrial dysfunction induced by AGEs and carbonyl intermediates may also contribute to the generation of superoxide 60 . Some studies have also suggested an important role for oxidative stress in RAGE-mediated signalling. This is illustrated by the finding that anti-oxidants are able to prevent the up-regulation of TGF 1 following exposure to AGEs 61 . Similarly, depletion of the endogenous...

Rodent Models Of Diabetes

Alloxan can be injected intravenously, intraperitoneally, or subcuta-neously. The dose required to induce diabetes depends on the animal species, route of administration, and nutritional status (21). After injection alloxan is taken up by the f -cells. Intracellularly, it gives rise to several processes, including oxidation of essential -SH groups, inhibition of glucokinase, generation of free radicals, and disturbances in intracellular calcium homeosta-sis (21). The selectivity of alloxan action for the f -cells is, however, not quite satisfactory. Alloxan is also taken up by other tissues, such as the liver. Although these other tissues appear to be more resistant to alloxan toxicity in

Cardiovascular Implications

However, other mechanisms could contribute to such effects gliclazide could also possess haemor-rheologic properties 70,71 . It reduces platelet reactivity, increases prostacyclin synthesis and increases fibrinolysis 9 . In one study, administration of either modified release or standard gliclazide to type 2 diabetic patients resulted in a fall in 8-isoprostanes, a marker of lipid oxidation, and an increase in total plasma antioxidant capacity, superoxide dismutase and thiols, all of them antioxidant parameters 72 . In a similar study, where these data were confirmed, gliclazide, but not glibenclamide reduced systolic and diastolic blood pressure 73 . Following that data, gliclazide possesses antioxidant properties that produce measurable clinical effects at therapeutic doses. In another study, gliclazide, but not glibenclamide treatment was able to lower serum ICAM-1 levels in poorly controlled type 2 diabetic patients, which typically have elevated serum ICAM-1 as a marker of...

Exogenous Sources of Advanced Glycoxidation End Products

About 10 of a single AGE-rich meal is absorbed into the body (24,25). Food-derived AGEs, rich in MG, CML, and other derivatives, are potent inducers of oxidative stress and inflammatory processes. As with endogenous AGEs these processes can be blocked by antioxidants and anti-AGE agents (26), pointing to many similarities (structural and biological) between exogenous and endogenous AGEs.

What is the relationship between cataract and DM

The polyol pathway has been incriminated in cataract production in experimental models of diabetic animals, with resultant accumulation of sorbitol and galctitol (a product of galactose) in the lens. This view is strengthened by the beneficial effect that aldose reductase inhibitors have on inhibition of this process and cataract formation, on condition these medicines are used early in diabetic patients. Furthermore, the role of lack of myoinositol or special aminoacids has been discussed, as well as the detrimental effect of free radicals, a view supported by the beneficial effect of antioxidant substances on delay or even prevention of cataract formation. The current prevailing view, however, for the mechanism of cataract formation is the enzymatic glycosylation of the lens contents and especially of the crystalline protein fibres. This process evolves at an accelerating pace in diabetes. At the same time the glycosylated crystalline fibres are more susceptible to...

Comparison Of Different Sulfonylureas And Meglitinides

Among sulfonylureas, no definitive advantages have been demonstrated for one compound compared with others in trials with hard endpoints. The potent long-acting sulfonylureas bear a higher risk of protracted hypoglycemias in elderly people who may miss meals, and in poorly controlled conditions. Shorter acting and less potent insulin releasers may be advantageous under these circumstances (16,28). Specific advantages have been proposed for gliclazide, due to its antioxidant actions, and glimepiride, due to its insulin sensitizing effects, both of which are of unknown significance (29,30).

Lipid Abnormalities and Lipid Lowering in Diabetes

Secretory Pathway Lipoprotein

IDL are in part converted into LDL (step 4 in figure 1) but in part are taken up and degraded by the liver (step 7 in figure 1) through another receptor (the remnant receptor) which is specific for ApoE, and is thought to be the LDL LRP. Thus, the VLDL-IDL-LDL pathway (steps 1-5 in figure 1) can be regarded as a pathway conveying C to peripheral tissues (including arteries), even if some amount of LDL-C is returned to liver (steps 1-4, 6 in figure 1). HDL, produced by liver (step 10 in figure 1) as well as by intestine (step not shown in figure 1) as native particles, are composed primarily of phospholipid, ApoA-I and ApoA-II, and other apoproteins. In the circulation, HDL can be distinguished into the larger and less dense HDL2 and the smaller and more dense HDL3. HDL serve important functions. They provide apoproteins (ApoC and ApoE) to VLDL (and chylomicrons) to allow the TG hydrolysis by LPL, and take up UC, phospholipid, and various apoproteins which form excess surface material...

Species of Plants Reported to Be Used Traditionally to Treat Diabetes

Decreases serum glucose, berberine has hypoglycemic activity (Chen and Xie, 1986) Decreases serum glucose, berberine has hypoglycemic activity (Chen and Xie, 1986) Used to treat diabetes (Maries and Farnsworth, 1995) Used to treat diabetes (Lewis, 1977) Volatile oil from seeds can reduce blood glucose via a mechanism that does not involve insulin. Also has antioxidant properties and decreases levels of lipid peroxidases (Ali and Blunden, 2003)

Pycnogenol and Grape Seed Extract

Pycnogenol (pronounced pick-noj'-in-nall) is a patented complex of about forty antioxidants, mostly proanthocyanidins (a family of flavonoids) and a variety of other antioxidants, including organic acids (such as cinnamic acids, caffeic acid, and ferulic acid). It is extracted from the bark of French maritime pine trees and sold under the Pycnogenol brand name by many different companies. The many different antioxidants in Pycnogenol make its sum far greater than any of its individual parts. Studies by Lester Packer, Ph.D., an antioxidant expert and professor emeritus at the University of California, Berkeley, have found that Pycnogenol is a powerful antioxidant. In addition to quenching free radicals, it also turns off some of the genes involved in producing inflammation. One study has found that Pycnogenol supplements reduced inflammation in patients with lupus erythematosus. Grape seed extracts are also rich in proanthocyanidins, though the specific types of antioxidants in this...

Where Do We Go New Antidiabetic Plants

The potential role of plants in treating or preventing the complications of diabetes, is mentioned in the chapters on Chinese and Kampo medicines, a Western herbalist's perspective, and flavonoids, xanthones, and other antioxidant polyphenols. This latter chapter and that on plant polysaccharides highlight the important role of dietary plant materials in the prevention and control of diabetes. Indeed, it is believed that changes in diet from traditional plant foodstuffs containing beneficial components to richer, more processed and junk food is responsible for the increasing prevalence of diabetes worldwide.

Endothelium Dependent Vasodilation in Animal Models

This is an increase in oxygen-derived free radicals (57), either because of an increase in free radical production or because of a decrease in the free radical scavenger system. Furthermore, free radical scavengers have been shown to improve the abnormal endot-helium-dependent vasodilation (58,59), implying that such free radicals may contribute to the abnormal endothelium-dependent relaxations.

Oxidative stress in health and disease

Oxidative stress is an underlying factor in health and disease. In this series of books, the importance of oxidative stress and diseases associated with organ systems of the body is highlighted by exploring the scientific evidence and clinical applications of this knowledge. This series is intended for researchers in the basic biomedical sciences and clinicians. The potential of such knowledge for healthy aging and disease prevention warrants further knowledge about how oxidants and antioxidants modulate cell and tissue function.

Obstacles to Success of Islet Allotransplantation

Poor engraftment is the first of these obstacles. The number of islets infused in a transplant procedure is far from matching the number of islets composing a normal endocrine pancreas (the recommended threshold of 6000 IEq kg represents 420,000 IEq in a 70-kg patient, i.e., less than half the one million islets of a human pancreas). Islets are an essentially avascular graft, which renders them particularly prone to hypoxia, at least during the time elapsing before neovessels revascularize the transplant (98,99). As already pointed out, a vast majority of islets are lost early after transplantation. The nonspecific events leading to early graft loss are collectively termed primary nonfunction and are not related to classic rejection immune phenomena. Rather, they result from poor intrinsic quality of the islet preparation or from interaction of the islets with inflammatory elements of the hepatic microenvironment in which they are implanted, a situation that does not occur in...

Vasoregulation Of Somatic Nerve Fibers


An early and consistent finding is impaired vasoregulation of peripheral nerve trunk. Nerve blood flow to peripheral nerve is reduced to about 50 of normal. The reduction occurs early and is sustained. In a recent review (1) of studies of peripheral nerve blood flow in experimental diabetic neuropathy, a reduction was demonstrated in 19 21 research programs (Table 1) and typically on multiple occasions. The two laboratories that failed to demonstrate this deficit had methodological problems such as inexperience with a label or contaminating nutritive flow with arteriovenous shunt flow. This reduction is because of impairment of nitric oxide synthase activity (2,3) and is initially reversible. To address the issue of whether the impaired perfusion is pathophysiologically important, Cameron et al. (4) regressed nerve blood flow against nerve conduction velocity. There is a close relationship between nerve blood flow and nerve conduction slowing (Fig. 1). This relationship highlights the...

Molecular Cell Biology Of Endothelial Dysfunction In Diabetes

High Glucose Insulin Pathway

Reactive oxygen species can affect many signalling pathways, such as G-proteins, protein kinases, ion channels and transcription factors, and may modify endothelial function by a variety of mechanisms. These include direct effects on the endothelium such as peroxidation of membrane lipids, activation of NF-kB, and interference with the availability of nitric oxide and indirect effects such as increasing the oxidation of LDL and the activation of platelets and monocytes. On the other hand, endothelial cells can respond to high glucose levels by increasing the expression of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase.

Mechanisms Of Hyperfiltration In Diabetes

Hemodynamically oriented studies have suggested that ROS, as renal vasoconstrictors, decrease bioavailability of NO or limit the buffering capacity of NO against vasoconstrictors 69-71 . Therefore, one would expect that the net effect of this imbalance would result in renal vasoconstriction. However, this is difficult to reconcile with the fact of diabetic hyperfiltration. Importantly, there is no evidence demonstrating the effect of ROS scavenging on basal arteriolar tone in diabetic rats 70 . Considering the NO-ROS interaction, one would expect enhanced afferent vasodilator responses to antioxidants in diabetes. In contrast, in vivo studies demonstrated that antioxidant treatment may normalize hyperfiltration in diabetes 64 . Considering the decrease in filtration fraction (FF) in diabetic rats treated with antioxidants, which was observed, one would expect efferent arteriolar effects of antioxidant treatment. These data suggest that these renal microvascular effects are...

Approach To The Surgical Patient With Hyperglycemia

Diabetic and non-diabetic patients develop hyperglycemia during surgery and medical illness due to enhanced hepatic gluconeogenesis, relative insulin deficiency, and decreased sensitivity of the liver, skeletal muscle, and adipose tissue to the actions of insulin (1-3). While clinical evidence suggests a direct association between hyperglycemia and adverse outcome in patients undergoing vascular and cardiac surgery, there is little prospective data available to indicate that glucose control improves outcome in the average hyperglycemic patient undergoing other types of surgical procedures (4-13). The adverse effects of hyperglycemia are mediated in large part by enhanced oxidative stress, which is not counter-balanced by endogenous antioxidants.

Treatments targeting Dagpkc pathway

In vitro, vitamin E (d-a-tocopherol), a well-known antioxidant, suppresses the DAG level in thrombinstimulated endothelial cells,103 and prevents the hyperglycaemia-induced activation of the DAG-PKC pathway in VSMC,104 by increasing the activity of DAG kinase,103,104 which lowers intracellular DAG levels by converting DAG to phosphatidic acid. d-a-Tocopherol does not affect purified PKCa and -p isoforms, indicating that vitamin E may act upstream to PKC.105 In experimental diabetes, vitamin E prevents the hyperglycaemia-induced increases of DAG and PKC levels in rat glomeruli, normalizes glomerular hyperfiltration, and improves UAE in STZ-induced diabetic rats.106 Furthermore, vitamin E has been shown to reduce the diabetes-associated increases in glomerular TGF-p immunoreactivity, and glomerular volume, but vitamin E has no effect on albumin clearance.107 In type 1 diabetic patients of short disease duration, oral vitamin E treatment normalizes elevated baseline creatinine clearance...

Hyperglycaemia And The Pathogenesis Of Diabetic Nephropathy

Diabetic Nephropathy Pathogenesis

Many studies have shown that diabetes and hyperglycaemia increase oxidative stress, but it was not known if it is an important early mediator of the high glucose effects on renal structures and functions. A recent study showed that high glucose increased the production of superoxide by the mitochondrial electron-transport chain in endothelial cells 81,92 . Inhibition of the generation of these reactive oxygen species (ROS) prevented the activation of PKC pathways, the increased flux through the HBP and the aldose reductase pathway, and the enhanced synthesis of AGEs. Whether this interference would also block high glucose-induced derranged production of glomerular matrix production is currently under investigation. It was demonstrated that mesangial cells grown in ambient high glucose produced ROS 93 , thus leading to activation of PKC, AP-1 and NF-kB, and the up-regulation of TGF- 1 and of matrix protein expression. The existence of glucose-induced oxidative stress in mesangial cells...

Activation of the Dagpkc Pathway

Pkc Insulin Resistance

It is also possible that DAG is produced through the metabolism of phosphatidylcholine as a result of the activation of phospholipase D (91). One potential pathway for the increase in DAG is the result of glyco-oxidation inducing activation of the DAG pathway because oxidants such as H2O2 are known to activate DAG-PKC pathway (Fig. 3) (92). We have reported that vitamin E, a well-studied antioxidant, has the additional interesting property of inhibiting the activation of DAG-PKC in vascular tissues and cultured vascular cells exposed to high glucose levels (74). We have confirmed that vitamin E can inhibit PKC activation probably by decreasing DAG levels rather than inhibiting PKC, because the direct addition of vitamin E to purified PKC-a or -P isoforms in vitro has no inhibitory effect (93).

Postprandial Hypoglycemia

Despite careful calculation of carbohydrate intake and insulin doses, continuous glucose sensing reveals that most people with type 1 diabetes experience large glucose fluxes (16), especially in the postprandial period. Growing evidence suggests that the risk for long-term vascular complications of diabetes may not be entirely explained by average glucose levels, as measured by the A1c (17). Glycemic exposure, as measured by A1c, age at diagnosis and duration of diabetes explains as little as one-third of the variability in the development of microvascular complications (18). Rather, the metabolic milieu associated with glycemic excursions may be additive to the effects of chronic hyperglycemia (17,19,20). Although hyperglycemia is associated with activation of many biochemical pathways known to have deleterious effects upon the endothelium, an imbalance between free radical production and antioxidant consumption (oxidative stress) appears to activate many of these pathways (20). If...

Causes of Type Diabetes

Insulin is produced by the beta cells in the pancreas. In people with type 1 diabetes, the immune system mistakenly destroys these cells. The body responds to the beta cells as if they were foreign invaders. This is called an autoimmune response. Autoimmune responses also occur in other diseases such as multiple sclerosis, lupus, and thyroid diseases such as hypothy-roidism (Hashimoto's disease) and hyperthyroidism (Graves' disease). Researchers do not know exactly why this happens. But for diabetes, researchers have found many factors that appear to be linked to type 1 diabetes. These include genetics, autoantibodies, viruses, cow's milk, and oxygen free radicals.

Treatment Of Painful Diabetic Neuropathy

There is accumulating evidence to support the role of oxidative stress in the pathogenesis of neuropathy. Studies with the antioxidant a-lipoic acid have provided evidence of potential efficacy for this agent which might well be beneficial both for neuropathic symptom relief, and for modifying the natural history of neuropathy (38,39).

Effects of PPARy Ligands Independent of Changes in Blood Glucose Levels

Transcription Factors Ppar

DAG-PKC-extracellular signal-regulated kinase (ERK) pathway is enhanced in MCs cultured with high glucose conditions and in glomeruli isolated from STZ-induced diabetic rats (93-96). D-a-Tocopherol (vitamin E), a well-known antioxidant agent, has been reported to reverse diabetic-induced renal dysfunction by modulating the activity of PKC signal transduction pathway and preventing the increased glomerular filtration and albumin excretion associated with diabetes (93). This effect was also thought to be owing to its antioxidant action in addition to the modulation of DAG kinase (DGK) activity (93,97). Increase in oxidative stress is observed in renal glomeruli and a variety of the vascular and nonvascular tissues exposed to hyperglycemia (99-101). Emerging evidence suggests that oxidative stress may contribute to the development of diabetic complications, possibly through activating DAG-PKC pathways. As stated before, D-a-tocopherol can inhibit the diabetes-induced activation of...

Diabetic Glomerulosclerosis

Diabetes Vascular Dysfunction

Oxidative stress has been implicated as a major determinant in the CVD and renal complications of DM (see Figs. 1-3). This stress results from the imbalance of the generation of ROS (i.e., superoxide, hydrogen peroxide, and hydroxyl radical formation) and the reduced antioxidant mechanisms (i.e., superoxide dismutase, catalase, and glutathione peroxidase) (see Fig. 3) (19). When there is an imbalance (as in a state of insulin resistance, CKD, and HTN), the increased ROS alters basic cellular proteins causing cellular damage and reduced endothelial-derived NO (20). Many of the pathways for formation of ROS are interrelated and are driven, in part, by PKC activation and enhanced NADPH oxidase activity, xanthine oxidase, and uncoupled NO synthase (16,21).

Alternative Hypothesis For The Hspg Alterations Findings From The Atherosclerosis Prospect

Alternative mechanisms can be put forward. There is growing evidence, that an imbalance in prooxidant and antioxidant activity and subsequent oxidative stress significantly contribute to the development and progression of renal disease. However, an oxidative imbalance is also a major actor of the endothelial dysfunction and enhanced vascular permeability in diabetes mellitus, a condition predisposing to atherosclerosis. Thus, the link between cardiovascular mortality and nephropathy in diabetes mellitus might well be related to the associated oxidative stress. 3. genes involved in the oxidative stress, i.e. in the AGE metabolism and turnover, or in the antioxidant defense systems.

In How Many Ways Can the pCells Get Killed Killing by Virus

Since Yoon et al. (131) isolated coxsackie B4 virus from the pancreas of a patient with type 1 diabetes, various viruses have been studied to examine their diabetogenic potential and to what extent viruses represent an environmental factor that contributes to the disease. The viral infection seems to be able to indirectly activate autoreactive T-cells that, in turn, can generate initial pancreatic tissue damage. Damaged P-cells release previously ignored self antigens that may activate an autoimmune process, rapidly promoting the generation of insulitis and, eventually, overt diabetes by immune-mediated P-cell killing. Viral infections could trigger type 1 diabetes through several mechanisms for example, (1) sequence similarities between islet-cell GAD65 and coxsackie virus could cause immune attack against coxsackie virus to also target the beta cells, (2) enteroviral infections could sustain autoimmunity until a final hit results in P-cell destruction following lysis of the cells,...

How is increased capillary permeability explained in DM

Production of free radicals from endothelial cells and white blood cells that accumulate in the region, leukotrienes production from white blood cells, LDL oxidation and release of IGF-1 (insulin-like growth factor-1), interleukin 1b, nitrous oxide and VEGF (vascular endothelial growth factor) from endothelial cells.

Measuring iron toxicity

In the early course of iron overload, numerous homeostatic mechanisms prevent damage from accumulating iron. These include increased ferritin production needed to sequester the labile iron, and increment in individual antioxidants and or antioxidant enzymes to protect against radical damage promoted by iron. However, these mechanisms might fail as more iron accumulates.

Oxidative stress in premature infants

Hypoxia Premature Infants

Premature infants are probably more prone to oxidative stress than term infants because premature infants very often are exposed to high oxygen concentrations as a result of pulmonary surfactant deficiency. They have lower and less efficient antioxidant defenses and more often are exposed to infections and inflammation resulting in the release of pro-inflammatory cytokines activating the production of ROS. Moreover, free iron is found in the plasma and tissues of premature infants at higher concentrations than in term infants.84 Several clinical studies in premature infants noted deficiencies in antioxidant defenses including lower cord blood SOD activities,85 lower concentrations of GSH in bronchoalveolar lavage fluid,86 and lower plasma GSH concentrations.87 Antioxidants such as vitamins E, A, and C, ceruloplasmin, transferrin, and trace metals such as copper, zinc, and selenium (metal cofactors required for antioxidant synthesis and activities) are low in preterm infants compared...

Etiology Of The Afferent Arteriolar Dilation Underlying Diabetic Hyperfiltration

H2o2 Redutcion

Of molecular oxygen by oxidases and auto-oxidation processes. As summarized in Fig. 2, O2'- formation leads to production of several ROS. The initial fate of O2'- is either dismutation to form hydrogen peroxide (H2O2) or reaction with nitric oxide (NO) to form peroxynitrite (ONOO-). Spontaneous dismutation of O2'- is accelerated more than 30,000-fold by superoxide dismutase (SOD), a reaction that proceeds at approx 60 of the rate of ONOO- formation (9). Significant amounts of H2O2 are produced that, in turn, can be degraded to H2O and O2 by antioxidant enzymes. Alternatively, H2O2 can serve as a precursor of other damaging substances such as hypochlorous acid (HOCl) and hydroxyl radical (OH). Whereas net accumulation of one or more ROS can result from excess formation and or inadequate degradation mechanisms (enzymatic and nonenzymatic scavengers and so on), the initiating event in this cascade is O2'- production. The cellular sources of O2'- include the mitochondrial electron...

CoQIO in heart disease

Although ubiquinol may inhibit the formation of oxidized and atherogenic forms of LDL, it is likely that the primary mechanism whereby CoQ10 could prevent heart disease is through its ability to improve ATP synthesis in cells with a high ATP demand such as cardiac myocytes. As an antioxidant, ubiquinol could also inhibit the free radical damage to the myocardium that arises during ischemia-reperfusion injury. Heart failure (due to cardiomyopathy and congestive heart failure), as discussed above, is a major and increasing worldwide health problem. It is logical to suggest that dietary CoQ10 supplementation could increase ATP production and thereby improve myocardial contractility. A meta-analysis of eight randomized controlled studies looking at the effect of dietary CoQ10 supplementation on congestive heart failure indicates an improvement in stoke volume, ejection fraction, cardiac output, cardiac index, and end diastolic volume index (Soja and Mortensen, 1997). These results...

Cell Adhesion Molecules

Mediators in turn promote the expression of adhesion molecules (93). Infusion of AGE products in rabbits produced a variety of vascular changes. In endothelial cells, these included increased expression of VCAM-1 and ICAM-1 mainly in areas affected by atheroma (93). Further supporting the significance of these interactions, it has been shown that blockade of receptor of advanced glycation end-products (RAGE) can inhibit AGE product-induced impairment of endothelial barrier function and consequent hyper-permeability. Inhibition of AGE product formation using antioxidants has a similar effect. More recently it has been shown that lesions from human coronary arteries from patients with diabetes when compared to lesions from nondiabetic patients, exhibit increased levels of an immunoreactive chemokine, fractalkine, that mediates firm adhesion of leukocytes (95).

Mechanisms Of Immunity In Diabetes

Several factors affecting the immune system may increase the susceptibility to infections in patients with diabetes mellitus. white blood cell abnormalities have been demonstrated in the form of impaired adherence, chemotaxis, phagocytosis, and microbicidal function (2,3). The intracellular killing of organisms by leukocytes is mediated by release of toxic free radicals, superoxides, and hydrogen peroxide. This phenomenon is referred to as the respiratory burst and is defective in patients with diabetes mellitus (4). Polymorphonuclear function is further affected by a state of persistent low-level activation by advanced glycation end products (AGEs). This hyperexcited

Symptomatic Treatment of Autonomic Neuropathy

Treatment of CAN is difficult due to its often hidden symptoms. Besides the ubiquitous recommendation of glycemic control, treatment is generally specific to the presentation of symptoms. Use of glycemic control, aspirin and angiotensin converting enzyme inhibitors for patients with microalbuminuria was shown to dramatically reduce CAN by a risk factor of 0.32 (88). Although this intervention was specific to T2DM, it may be applicable to T1DM. Other experimental techniques for broad reduction of CAN include the use of antioxidants (a-lipoic acid) or aldose reductase inhibitors. While many aldose reductase inhibitor trials have been withdrawn due to adverse or only marginal effects, the clinical trial of epalrestat showed optimistic results. In this study, epalrestat was well-tolerated, delayed onset of CAN, and ameliorated some symptoms (89).

Role For Vascular Vs Nonvascular Mechanisms

The vascular concept of PDN is seemingly supported by the recent findings with the high molecular weight metal chelator, hydroxy ethyl starch-deferoxamine (HESD), known to be confined to vascular space when administered intravenously and therefore, not to penetrate into neural elements of the peripheral nerve. Alleviation of both NBF and nerve conduction deficits (22,23), combined with reduced superoxide and peroxyni-trite formation in vasa nervorum (23), in HESD-treated streptozotocin (STZ)-diabetic rats in comparison with the corresponding untreated group could be interpreted as a proof for the key role of vascular mechanism in MNCV and SNCV deficit in early diabetes. However, it is not excluded that in vascular space, HESD is metabolized with formation of deferoxamine, with its subsequent delivery to a neural compartment of the peripheral nerve. In addition, such reactive oxygen species (ROS) as hydrogen peroxide, lipid peroxide (free form), and peroxynitrite can move from vascular...

The functional properties of ubiquinone CoQIO in preventing heart disease

Ubiquinone or CoQ is a lipid-soluble micronutrient present in animal cells and in many plants. Ubiquinol is the reduced form of CoQ and it functions as an antioxidant as further detailed below (Frei et al., 1990). CoQ can be synthesized in vivo and is not, therefore, a true vitamin. There are, however, circumstances in which the utilization of CoQ surpasses its rate of synthesis. For example, the use

Risk factors for coronary heart disease CHD the role of oxidative stress

Endothelial Dysfunction Diabetic Foot

Different stage in a chronic inflammatory process in the artery. The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can be described as an inflammatory disease. Possible causes of endothelial dysfunction leading to atherosclerosis include hypercholesterol-aemia, hypertension, diabetes mellitus, cigarette smoking, elevated plasma homocysteine concentrations, infectious microrganisms and ageing. Framingham's studies have shown how each factor and combination of these factors are associated with atherosclerotic diseases.9 All these factors can be associated with oxidative stress.10-15 The beneficial effect of alpha-tocopherol and ascorbic acid is mediated by their antioxidant actions in preventing atherosclerosis. On the other hand, the effect of alpha-tocopherol could also be mediated by its antiplatelet and anti-coagulant actions, which would prevent the thrombotic consequences of atherosclerosis.16'17 Cigarette smoking,...

Dietary Modifications

A significant body of epidemiologic evidence associates certain dietary patterns with an increased risk of cancer 47 . In addition to eating for maximum regulation of glycemic response and for gut health, and eliminating other inflammation-promoting foods like high fructose corn syrup and trans-fats, it is prudent for someone with existing diabetes to follow the dietary patterns associated with decreased cancer risk. A diet rich in fat and meat, and low in fiber, fruits, and vegetables, is associated with an increased risk of colorectal, mammary, and other common forms of cancer. Links between high glycemic index and glycemic load to the development of various cancers have been reported. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalances of w-3 and w-6 fats all contribute to excess cancer risk. Intake of EFA and abundant...

Prevention Of Type Diabetes

Interventions have been targeted at altering a number of behavioral factors including obesity, dietary intake and physical activity. Obesity, of course, should be considered the result of behavioral, genetic and physiological factors and not simply behavioral. Pharmacological interventions have primarily used hypoglycemic or anti-hyperglycemic medication to reverse insulin resistance (biguanides, thiazolidenediones), failure of insulin secretion (sulfonylureas), or glycemic excursions (alpha-glucosidase inhibitors). Trials have attempted to alter glucose metabolism using metal supplementation (magnesium, chromium) or antioxidants (beta-carotene, vitamin E). Trials that have used

Recent Developments

3 A major theme of current nutritional research is the interaction between dietary components and the expression of genes or the activity of metabolic pathways in vivo. Conjugated linoleic acids have been proposed as regulators of lipid metabolism and insulin resistance.7 There has been interest in diets that include a small amount of walnuts.8 These contain a high proportion of polyunsaturated fats including a-linoleic acid as well as the antioxidant 7-tocopherol. Compared with a control diet, a diet that included 30 grams of walnuts per day significantly increased HDL-cholesterol and decreased LDL-cholesterol.

Therapies Targeted To Metabolic Pathways

Inos Ldiabetes

Note The aldose reductase inhibitors are discussed elsewhere (see Chapter 18). Antioxidants Hyperglycemia has been shown in a number of studies to cause oxidative stress in tissues that are susceptible to the complications of diabetes, including peripheral nerves. In turn, the oxidative stress leads to the generation of free radicals that can attack the lipids, proteins, and nucleic acids of the affected tissues directly, compromising physiological function. The end result is the loss of axons and disruption of the microvascu-lature in the peripheral nervous system (Fig. 2). It has been shown that there is an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant moieties were reduced in patients with diabetic peripheral neuropathy (4). Therefore, it is reasonable to use therapies that are known to reduce oxidative stress in tissues, and antioxidants. Although a host of antioxidants have been tested in animal models (for...

T Dry Steamed billed Carrots

Here's a tasty twist on a veggie favorite. Heather Dismore uses fresh herbs here to give these carrots a new and interesting flavor. Carrots are one of the best sources of vitamin A, antioxidants, lutein, and beta carotene. These are the nutrients best known for eye health. The orange fruits and vegetables are all good sources of these antioxidants, so get them in whenever you can

Anemia As A Progression Promoter In Diabetic Nephropathy

A major consequence of anemia is an increase in oxidative stress (25), a key mediator in the development and progression of diabetic renal disease. This may be mediated by the loss of antioxidant properties of erythrocytes including the enzymes superoxide dismutase, catalase, and other antioxidant proteins. In addition, renal anemia is associated with increased production of free radicals. It is conceivable that the combination of increased oxidative stress and tissue hypoxia associated with anemia may act to stimulate the production of extracellular matrix, increasing interstitial fibrosis and tubular apoptosis, and lead to tubular atrophy associated with progressive renal disease.

Broccoli and Cheese

Broccoli is one of the best sources of antioxidants out there, meaning it's full of disease-fighting agents. It's great fresh, steamed, baked, or microwaved. If possible, avoid boiling it in liquid that you'll later discard, because you remove too many of its healthy nutrients. Enjoy it in this cheesy crust-free pie.

The Diabetes Damage Cascade

Glycated proteins cause damage to cells in numerous ways, including impairing cellular function, which induces the production of inflammatory cytokines (Wright E Jr. et al 2006) and free radicals (Forbes JM et al 2003 Schmidt AM et al 2000). complication of diabetes, a 21 percent reduction in deaths related to diabetes, a 14 percent reduction in heart attack, and a 37 percent reduction in microvascular complications (Stratton IM et al 2000). High levels of blood glucose and glycation also produce free radicals that further damage cellular proteins (Vincent AM et al 2005) and reduce nitric oxide levels.

Human milk and antioxidative protection

Human milk (HM) is considered the ideal food for healthy infants129 and is known to contain various bioactive substances, some of which are reported to be anti-oxidants.130 HM contains many antioxidants such as enzymes (CAT, GPx, SOD), vitamins (A, C, E), binding proteins such as lactoferrin, and constituents of antioxidative enzymes (Cu, Zn).131-133 In contrast, antioxidative enzymes are absent from infant formula.134 Most infant formula has higher amounts of vitamins added than are present in HM to make up for the reduced bioavailability. Thus, the overall antioxidant capacity of HM versus infant formula is difficult to assess, although assessment would probably favor HM.14 We previously reported in vitro results showing that HM alleviated H2O2-induced oxidative damage in intestinal epithelial cell lines, whereas bovine milk or infant formula did not.135 Confluent intestinal epithelial (IEC-6) cells were preincubated with defatted HM, bovine milk, or three artificial milks for 24 hr...

Functional foods defined

Functional foods that are marketed with claims to reduce heart disease focus primarily on the risk factors of blood cholesterol, homocysteine and hypertension. This can be done by a reduced content of food components that are known to increase risk, such as saturated fat or sodium. More recently products have been designed that are enriched in components that are thought to reduce risk. The most common 'protective' ingredients include fibres, soya, omega-3 fatty acids, phytostanols and phytosterols, and (antioxidant) vitamins. These components have cholesterol or homocysteine-lowering abilities in metabolic studies. The added ingredients may be food components that are often deficient in Western diets, such as calcium and folate. Their recommended intake could, however, be achieved by 'normal' foods. The added ingredients may also be nutrients or phytochemicals that are normally

How Vitamin E Reduces Inflammation

During the 1990s it became clear that high levels of the low-density lipoprotein (LDL) form of cholesterol increased the risk of heart disease. Basically, the idea is that LDL appears to be neutral until it is oxidized, or damaged by free radicals. It has become fashionable to describe LDL as the bad form of cholesterol, but this is a misnomer because it is not inherently unhealthy. LDL is necessary for transporting vitamin E and other fat-soluble nutrients through the blood. In other words, these antioxidants should normally be present in LDL and prevent its oxidation. LDL oxidation occurs when dietary vitamin E and other antioxidants are insufficient, or when there is a large amount of cholesterol relative to vitamin E. Free radicals stimulate and amplify inflammatory reactions through a number of mechanisms. For example, free radicals activate some of the genes involved in inflammation. They also turn on a variety of adhesion molecules, which, as the term suggests, encourage white...

Diabetes And Minerals Vitamins And Dietary Supplements

It is important for patients with diabetes to be counseled about the importance of consuming adequate amounts of minerals and vitamins from natural food sources and to be aware of the potential toxic effects of megadoses of vitamin and mineral supplements. Interest in antioxidant vitamins in people with diabetes has increased with the knowledge that diabetes may be a state of increased oxidative stress. At present, megadoses of dietary antioxidants, such as selenium, P-carotene, vitamin E, and vitamin C, have not demonstrated cardioprotection in diabetic patients in some clinical trials, such as the Heart Outcomes Prevention Evaluation (HOPE) trial, they have actually been shown to be inferior to certain medications, particularly angiotensin-converting enzyme (ACE) inhibitors (16). Antioxidants significantly retard or inhibit this destructive oxidative process. Certain antioxidants are endogenous, such as ferritin, transferrin, and urate, whereas other antioxidants are acquired. 1....

Pathogenesis Of Dpn And

These alterations in cellular metabolism result in peripheral nervous system damage and the signs and symptoms of DPN. In the diabetic rat, measures of oxidative stress and reduced levels of circulating antioxidants parallel DPN, and blocking oxidative stress in the diabetic animal prevents the development of DPN. Antioxidants restore normal blood flow and sciatic and saphenous nerve conduction velocities in streptozo-tocin (STZ) diabetic rats (9,11-14,16). Treatment with insulin decreases ROS activity in diabetes and prevents DPN (10-12). Antioxidant therapy may ameliorate DPN and DAN in man. Lipid peroxidation measured as increased serum lipid peroxides is a marker of oxidative stress and is well documented in diabetic patients with microvas-cular complications (19).

Role For Oxidativenitrosative Stress

8-hydroxy-2'-deoxyguanosine in DRG of STZ-diabetic rats (19). Diabetes-induced changes of the aforementioned indices were corrected by antioxidant treatment. Accumulation of nitrotyrosine (a footprint of peroxynitrite-induced protein nitration) has been documented in peripheral nerve (45), vasa nervorum (23,45), and DRG (93) in diabetic rats, and peripheral nerve of diabetic mice (92) indicating that diabetes creates not just oxidative, but oxidative-nitrosative stress in PNS. Enhanced nitrosative stress has been documented in human subjects with PDN (95). Numerous new studies reveal the important role of oxidative stress in nerve functional, metabolic, neurotrophic, and morphological abnormalities characteristic of PDN. The role for ROS in diabetes-associated nerve conduction and blood flow deficits has been demonstrated in studies with the universal antioxidant DL-a-lipoic acid (5,23,91), which is known to combine free radical and metal chelating properties with an ability (after...

Course Of Nephropathy During Pregnancy

In a New Zealand study of pooled groups of 100 each of type 1 and 2 diabetes, significant factors predicting the development of hypertension in pregnancy included nulliparity (RR 1.5), smoking (RR 0.39), duration diabetes 10 years (RR 1.87), earliest HbA1c 9.0 (RR 1.9), retinopathy (RR 1.8), earliest UAE 30-300 mg 24hr (RR 1.8), earliest systolic BP 116-129 mmHg or higher (RR 2.1), and earliest diastolic BP 80 mmHg (RR 2.5) 175 . Many of these parameters are interelated. Primary PET was more common in type 1 (19 ) than in type 2 (7 ) diabetes, while the latter cases had more chronic hypertension and micro- and macroalbuminuria. Similar predictors of hypertensive disorders in pregnant women with type 1 diabetes were identified in large Swedish and North American multicenter studies 176-178 . Initial hypertension in women with DN is a strong predictor of cross-over from a hyperdynamic hemodynamic state with increased cardiac output to vasoconstriction associated with PET and decline in...

Chapter The consequences of uncontrolled diabetes

Oxidative stress is also central to the damage caused by diabetes. Diabetics suffer from high levels of free radicals that damage arteries throughout the body, from the eyes to the heart. Once again, it is important that diabetics understand their need for antioxidant therapy to help reduce oxidative stress and lower the risk of diabetic complications.

Clinical Trials of Human Islet Allotransplantation

Strategies based on observations made in experimental animal models, namely the use of endotoxin-free reagents, the use of antioxidant agents (nicotinamide), and the administration of intravenous insulin starting 2-3 d prior to transplant in order to diminish metabolic demand on the graft. With this protocol, insulin independence has been achieved in approx 30 of transplanted patients (118,119). In a recent report from the Geneva group, who implemented peritransplant management along the same lines, graft function for 3 mo to 5 yr was demonstrated in all of 13 consecutive type 1 diabetic recipients of islet allografts (120).

What Else Might Help

Other antioxidants also may offer protection against H. pylori infections and their consequential damage to the stomach. Among these are the herb Ginkgo biloba and garlic. Lycopene, a carotenoid that gives tomatoes their red color, has been associated with a relatively low risk of stomach cancer, though this association does not directly prove prevention. In addition, animal experiments suggest that food allergies also might irritate the stomach and lead to gastritis and ulcers.

Victor Olympic Nutrition

S0ren Mavrogenis, the physiotherapist for the Danish Olympic team, began recommending a combination of omega-3 fatty acids, gamma-linolenic acid, and antioxidants in 1996. At the time he had been treating the inflamed knee of a female rower but had not been able to help her. Because of the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), Mavrogenis was reluctant to recommend them for long-term use. Mavrogenis's conversations with health writer Bj0rn Falck Madsen and a researcher at a Scandinavian vitamin company led to a specific supplement regimen. The rower started taking the supplements and was able to resume rowing within a few weeks. One success led to another, and today Mavrogenis routinely uses a combination of omega-3 fatty acids, gamma-linolenic acid, and antioxidants (brand name Bio-Sport), along with deep muscle massage, to treat chronic overuse and inflammatory disorders. About one-third of his clinic's patients are elite athletes. One of Mavrogenis's...

The Inflammation Syndrome Connection

The high-sugar and high-carbohydrate diets that lead to obesity raise glucose levels, and elevated glucose spontaneously generates large numbers of free radicals. These free radicals stimulate the inflammatory response, which can increase the risk of coronary artery disease, cancer, Alzheimer's, and many other diseases. In addition, abdominal fat cells secrete large quantities of pro-inflammatory interleukin-6 and C-reactive protein. In overweight and obese people both of these substances help maintain a state of chronic inflammation.

Nutrients That Can Help

S0ren Mavrogenis, a physiotherapist in Copenhagen and the physical therapist for the Danish Olympic team, uses a combination of fatty acids and antioxidants to treat injuries among Olympians and other elite athletes. The fatty acids include omega-3 fish oils (706 mg daily), gamma-linolenic acid (670 mg daily), and modest amounts of antioxidant vitamins and minerals. In one of several controlled studies, S0ren and Norwegian physicians treated forty recreational athletes, men and women eighteen to sixty years old, with the fatty acid antioxidant supplement or placebos for one month. All of the subjects had suffered overuse injuries in sports activities, experiencing chronic inflammation for at least three months before entering the study. In addition to the supplements and placebos, the subjects also received physical therapy. Nearly all of the participants had significant reductions in their inflammation and pain. Exercise is well documented for increasing levels of free radicals,...

The Natural History Of Type Diabetes

Aldose reductase is an enzyme that causes accumulation of sorbitol at the cellular level in various diabetic conditions. Sorbitol accumulation directly leads to tissue damage and promotes the macro- and microvascular complications of diabetes because excess intracellular sorbitol levels decrease the concentration of various protective organic osmolytes. This is seen in the animal model of cataracts that contain decreased levels of taurine, a potent antioxidant and free-radical scavenger. Interestingly, inhibitors of aldose reductase have restored levels of protective osmolites and prevented diabetic complications by diminishing sorbitol reduction (13). The hyperglycemic state induces the formation of harmful free radicals, increasing oxidative stress through nonenzymatic reactions and enzymatic processes. This oxidative stress results from a chemical imbalance between the reactive oxygen species known as free radicals and the endogenous cellular defenses against them. The presence of...

Therapeutic targets for reducing oxidant stress in overweight and obese patients

Antioxidants One potential therapy to reduce oxidant stress in vivo is antioxidant supplementation. Animal and human epidemiologic studies carried out in the 1980s and 1990s suggested that antioxidants decreased atherosclerosis, presumably by reducing oxidant stress. However, prospective clinical trials of antioxidant supplementation using vitamin E and other agents have been disappointing and yielded conflicting results.43-47 Three large trials, ATBC, GISSI, and HOPE, involving tens of thousands of subjects, failed to show reductions of cardiovascular events when vitamin E was used at doses ranging from 50 to 400 IU day.47-50 On the other hand, two trials, CHAOS and SPACE, involving fewer subjects, reported near 50 reductions in the incidence of cardiovascular events with supplementation with 800 IU day.5152 All these studies suffer from the limitation of using only cardiovascular events as trial endpoints and not assessing oxidant stress in study participants. Thus, it is impossible...